Alzheimer's Disease Assessment Research Articles

Role of vitamin B12 and folic acid in treatment of Alzheimer's disease: a meta-analysis of randomized control trials.

Vitamin B12 and folic acid could reduce blood homocysteine levels, which was thought to slow down the progression of Alzheimer's disease (AD), but previous studies regarding the effect of vitamin B12 and folic acid in treatment of AD have not reached conclusive results. We searched PubMed and Embase until January 12, 2023. Only randomized control trials involving participants clearly diagnosed with AD and who received vitamin B12 and folic acid were enrolled. Five studies that met the criteria were selected for inclusion in the meta-analysis. Changes in cognitive function were measured based on either the Mini-Mental State Examination (MMSE) or the Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog). Changes in daily life function and the level of blood homocysteine were also investigated. After a 6-month treatment, administration of vitamin B12 and folic acid improved the MMSE scores more than placebo did (SMD = 0.21, 95% CI = 0.01 to 0.32, p = 0.04) but did not significantly affect ADAS-Cog scores (SMD = 0.06, 95% CI = -0.22 to 0.33, p = 0.68) or measures of daily life function. Blood homocysteine levels were significantly decreased after vitamin B12 and folic acid treatment. Participants with AD who received 6 months of vitamin B12 and folic acid supplementation had better MMSE scores but had no difference in ADAS-Cog scores. Daily life function did not improve after treatment.

Improving Regression Analysis with Imputation in a Longitudinal Study of Alzheimer's Disease.

Missing data is prevalent in the Alzheimer's Disease Neuroimaging Initiative (ADNI). It is common to deal with missingness by removing subjects with missing entries prior to statistical analysis; however, this can lead to significant efficiency loss and sometimes bias. It has yet to be demonstrated that the imputation approach to handling this issue can be valuable in some longitudinal regression settings. The purpose of this study is to demonstrate the importance of imputation and how imputation is correctly done in ADNI by analyzing longitudinal Alzheimer's Disease Assessment Scale -Cognitive Subscale 13 (ADAS-Cog 13) scores and their association with baseline patient characteristics. We studied 1,063 subjects in ADNI with mild cognitive impairment. Longitudinal ADAS-Cog 13 scores were modeled with a linear mixed-effects model with baseline clinical and demographic characteristics as predictors. The model estimates obtained without imputation were compared with those obtained after imputation with Multiple Imputation by Chained Equations (MICE). We justify application of MICE by investigating the missing data mechanism and model assumptions. We also assess robustness of the results to the choice of imputation method. The fixed-effects estimates of the linear mixed-effects model after imputation with MICE yield valid, tighter confidence intervals, thus improving the efficiency of the analysis when compared to the analysis done without imputation. Our study demonstrates the importance of accounting for missing data in ADNI. When deciding to perform imputation, care should be taken in choosing the approach, as an invalid one can compromise the statistical analyses.

REsveratrol for VAscular cognitive impairment investigating cerebral Metabolism and Perfusion (REVAMP trial): a study protocol for a randomized, double-blind, placebo-controlled trial.

Carotid artery stenosis or occlusion (CASO) is a major cause of vascular cognitive impairment (VCI). There is currently no effective treatment for VCI induced by CASO. Resveratrol, a type of polyphenol, improves cognitive performance in rat CASO models via pleiotropic effects. Furthermore, we previously reported the longevity gene, SIRT1, which can be activated by resveratrol, improves cognitive and cerebral blood flow impairment in mouse CASO models by activating endothelial nitric oxide synthase. However, clinical evidence remains limited. The REsveratrol for VAscular cognitive impairment investigating cerebral Metabolism and Perfusion (REVAMP) trial is a randomized, double-blind, placebo-controlled trial involving patients with asymptomatic CASO. Each participant will receive either 150 mg/day of resveratrol or a placebo for 35 weeks. The primary objective is to determine whether resveratrol improves cognitive impairment, as assessed using the Alzheimer's disease Assessment Scale-cognitive subscale 13. One of our secondary objectives is to determine whether resveratrol improves cerebral hemodynamic impairment as assessed via 15O-gas positron emission tomography. We will recruit 100 patients (50 per group). The REVAMP trial may provide valuable insights into new therapeutic options, as multitarget neuroprotection could potentially improve cognitive function along with enhancements in cerebral hemodynamic status in patients with asymptomatic CASO.Clinical trial registration: The REVAMP trial was prospectively registered in the Japan Registry of Clinical Trials (jRCTs051230013) on April 13, 2023.

Machine Learning-Based Perivascular Space Volumetry in Alzheimer Disease.

Impaired perivascular clearance has been suggested as a contributing factor to the pathogenesis of Alzheimer disease (AD). However, it remains unresolved when the anatomy of the perivascular space (PVS) is altered during AD progression. Therefore, this study investigates the association between PVS volume and AD progression in cognitively unimpaired (CU) individuals, both with and without subjective cognitive decline (SCD), and in those clinically diagnosed with mild cognitive impairment (MCI) or mild AD. A convolutional neural network was trained using manually corrected, filter-based segmentations (n = 1000) to automatically segment the PVS in the centrum semiovale from interpolated, coronal T2-weighted magnetic resonance imaging scans (n = 894). These scans were sourced from the national German Center for Neurodegenerative Diseases Longitudinal Cognitive Impairment and Dementia Study. Convolutional neural network-based segmentations and those performed by a human rater were compared in terms of segmentation volume, identified PVS clusters, as well as Dice score. The comparison revealed good segmentation quality (Pearson correlation coefficient r = 0.70 with P < 0.0001 for PVS volume, detection rate in cluster analysis = 84.3%, and Dice score = 59.0%). Subsequent multivariate linear regression analysis, adjusted for participants' age, was performed to correlate PVS volume with clinical diagnoses, disease progression, cerebrospinal fluid biomarkers, lifestyle factors, and cognitive function. Cognitive function was assessed using the Mini-Mental State Examination, the Comprehensive Neuropsychological Test Battery, and the Cognitive Subscale of the 13-Item Alzheimer's Disease Assessment Scale. Multivariate analysis, adjusted for age, revealed that participants with AD and MCI, but not those with SCD, had significantly higher PVS volumes compared with CU participants without SCD (P = 0.001 for each group). Furthermore, CU participants who developed incident MCI within 4.5 years after the baseline assessment showed significantly higher PVS volumes at baseline compared with those who did not progress to MCI (P = 0.03). Cognitive function was negatively correlated with PVS volume across all participant groups (P ≤ 0.005 for each). No significant correlation was found between PVS volume and any of the following parameters: cerebrospinal fluid biomarkers, sleep quality, body mass index, nicotine consumption, or alcohol abuse. The very early changes of PVS volume may suggest that alterations in PVS function are involved in the pathophysiology of AD. Overall, the volumetric assessment of centrum semiovale PVS represents a very early imaging biomarker for AD.

The associations of serum isoleucine with Alzheimer`s disease on assisting diagnosis, predicting conversion and assessing cognition.

Advances in blood biomarker discovery have enabled the improved diagnosis and prognosis of Alzheimer's disease (AD). Most branched-chain amino acids, except isoleucine (Ile), are correlated with both mild cognitive impairment (MCI) and AD. Therefore, this study investigated the association between serum Ile levels and MCI/AD. This study stratified 700 participants from the Alzheimer's Disease Neuroimaging Initiative database into four diagnostic groups: cognitively normal, stable MCI, progressive MCI, and AD. Analysis of covariance and chi-square analyses were used to test the demographic data. Receiver operating curve analyses were used to calculate the diagnostic accuracy of different biomarkers and were compared using MedCalc 20. Additionally, Cox proportional hazards models were used to measure the ability of serum Ile levels to predict disease conversion. Finally, a linear mixed-effects model was used to evaluate the associations between serum Ile levels and cognition, brain structure, and metabolism. Serum Ile concentration was decreased in AD and demonstrated significant diagnostic efficacy. The combination of serum Ile and cerebrospinal fluid (CSF) phosphorylated tau (P-tau) levels improved the diagnostic accuracy in AD compared to T-tau alone. Serum Ile levels significantly predicted the conversion from MCI to AD (cutoff value = 78.3 μM). Finally, the results of this study also revealed a correlation between serum Ile levels and the Alzheimer's Disease Assessment Scale cognitive subscale Q4. Serum Ile level may be a potential biomarker of AD. Ile had independent diagnostic efficacy and significantly improved the diagnostic accuracy of CSF P-tau in AD. Patients with MCI with a lower serum Ile level had a higher risk of progression to AD and a worse cognition assessment.

The association of the 24-hour activity cycle profiles with cognition in older adults with mild cognitive impairment: A cross-sectional study.

The relationship of cognition and the 24-hour activity cycles (24-HAC), encompassing physical activity, sedentary behaviour, and sleep, in older adults with mild cognitive impairment (MCI) remains uncertain. Distinct combinations of 24-HAC behaviours can characterize unique activity profiles and influence cognition. We aimed to characterize 24-HAC activity profiles in older adults with MCI and assess whether differences in cognition exist across profiles. We conducted a cross-sectional analysis utilizing baseline data from three randomized controlled trials involving 253 community-dwelling older adults (55+ years) with MCI (no functional impairment, dementia diagnosis, and Montreal Cognitive Assessment score <26/30). Using MotionWatch8© wrist-worn actigraphy (+5 days), we captured the 24-HAC. Cognition was indexed by the Alzheimer's Disease Assessment Scale Cognitive Plus (ADAS-Cog-Plus). Compositional data and latent profile analyses identified distinct 24-HAC activity profiles. Analysis of covariance examined whether 24-HAC activity profiles differed in cognition. Four distinct activity profiles were identified. Profile 1 ("Average 24-HAC," n=108) engaged in all 24-HAC behaviours around the sample average. Profile 2 ("Active Chillers," n=64) depicted lower-than-average engagement in physical activity and higher-than-average sedentary behaviour. Profile 3 ("Physical Activity Masters," n=56) were the most active and the least sedentary. Profile 4 ("Sedentary Savants," n=25) were the least active and the most sedentary. Sleep was similar across profiles. There were no significant differences in ADAS-Cog-Plus scores between 24-HAC activity profiles (p>0.05). Older adults with MCI exhibited four 24-HAC activity profiles conforming to recommended physical activity and sleep guidelines. Nonetheless, cognition was similar across these profiles.

Short-term memory binding is insensitive to the socioeconomic status of older adults with and without mild cognitive impairment

Objective: The Visual Short-Term Memory Binding (VSTMB) Test is a useful tool in the assessment of Alzheimer’s disease (AD). Research has suggested that short-term memory binding is insensitive to the sociocultural characteristics of the assessed individuals. Such earlier studies addressed this influence by considering years of education. The current study aims to determine the influence of sociocultural factors via a measure of Socioeconomic Status (SES) which provides a more holistic approach to these common confounders. Methods: A sample of 126 older adults, both with (n = 59) and without (n = 67) amnestic mild cognitive impairment (aMCI), underwent assessment using a neuropsychological protocol including VSTMB test. All participants were classified as either high SES or low SES, employing the Standard Demographic Classification from the European Society for Opinion and Marketing Research. Results: ANOVA/ANCOVA models confirmed that performance of healthy and aMCI participants on traditional neuropsychological tests were sensitive to SES whereas the VSTMB Test was not. The results add to the growing array of evidence suggesting that there are cognitive abilities which are unaffected by socioeconomic factors, regardless of clinical condition. Conclusions: The lack of sensitivity to sociocultural factors previously reported for the VSTMB test is accompanied by a lack of sensitivity to socioeconomic factors thus broadening the scope of this test to aid in the detection of dementia across populations with different backgrounds. Future studies should take these findings forward and explore the potential influences of AD biomarkers (A/T/N) on the association between cognitive functions and demographic variables.

Lecanemab Questions.

The recently published results of the 18-month randomized controlled trial of lecanemab, reporting the efficacy of the drug in slowing the progression of early Alzheimer disease, quickly led to approval by the FDA and widespread acceptance of lecanemab treatment. However, there are a number of matters that deserve further consideration. The success of blinding was not assessed, even as infusion reactions and the cerebral pathology underlying amyloid-related imaging abnormalities could have signaled to many participants that they were on drug, potentially exerting a potent placebo effect. The value of the outcome to participants is not defined in the absolute terms necessary for clinical decision-making, and the difference attributable to lecanemab was between 18% and 46% of estimates of the minimal clinically important difference on the Clinical Dementia Rating Scale Sum of Boxes. The attenuation of change on the Alzheimer's Disease Assessment Scale-Cognitive 14 achieved by lecanemab at 18 months was 50% of that achieved by donepezil at 6 months. Lecanemab treatment imposes a high treatment burden. The fact that the burden commences at the initiation of lecanemab treatment, whereas the benefit accrues years later requires us to take into account value discounting over time, which would significantly reduce the benefit/burden ratio. Finally, treatment with monoclonal antibodies to cerebral amyloid has consistently been associated with progressive cerebral atrophy. At the least, these issues should be raised in treatment discussions with patients. They also suggest a need to very seriously reconsider how we evaluate clinical trial results preparatory to translating them into clinical practice. Some suggestions are provided.

The impact of informant-related characteristics including sex/gender on assessment of Alzheimer's disease symptoms and severity.

The impact of informant-related characteristics including sex/gender on assessment of Alzheimer's disease symptoms and severity.

Clinical utility of plasma Aβ42/40 ratio by LC-MS/MS in Alzheimer's disease assessment.

Plasma Aβ42/40 ratio can help predict amyloid PET status, but its clinical utility in Alzheimer's disease (AD) assessment is unclear. Aβ42/40 ratio was measured by LC-MS/MS for 250 specimens with associated amyloid PET imaging, diagnosis, and demographic data, and for 6,192 consecutive clinical specimens submitted for Aβ42/40 testing. High diagnostic sensitivity and negative predictive value (NPV) for Aβ-PET positivity were observed, consistent with the clinical performance of other plasma LC-MS/MS assays, but with greater separation between Aβ42/40 values for individuals with positive vs. negative Aβ-PET results. Assuming a moderate prevalence of Aβ-PET positivity, a cutpoint was identified with 99% NPV, which could help predict that AD is likely not the cause of patients' cognitive impairment and help reduce PET evaluation by about 40%. High-throughput plasma Aβ42/40 LC-MS/MS assays can help identify patients with low likelihood of AD pathology, which can reduce PET evaluations, allowing for cost savings.

The Effect of Psychological Resilience on Cognitive Decline in Community-Dwelling Older Adults: The Korean Frailty and Aging Cohort Study.

Chronic stress is associated with an increased risk of cognitive impairment and Alzheimer's disease. This study aimed to assess whether better coping with stress, as assessed using the Brief Resilience Scale (BRS), is associated with slower cognitive decline in community-dwelling older adults. This study used 2018/2019 data and 2-year follow-up data from the Korean Frailty and Aging Cohort Study. Of the 3,014 total participants, we included 1,826 participants (mean age, 77.6±3.7 years, 51.9% female) who completed BRS and Korean version of the Consortium to Establish a Registry for Alzheimer's Disease Assessment Battery and the Korean version of the Frontal Assessment Battery (FAB). Higher BRS score at baseline was associated with a lesser decline in the Mini-Mental State Examination score over 2 years after adjusting for age, sex, years of education, smoking status, hypertension, diabetes, and depression (B, 0.175; 95% confidence interval, 0.025-0.325) for 2 years, which represents global cognitive function. Other cognitive function measurements (Word List Memory, Word List Recall, Word List Recognition, Digit Span, Trail Making Test-A, and FAB) did not change significantly with the BRS score at baseline. These findings suggest that better stress-coping ability, meaning faster termination of the stress response, may limit the decline in cognitive function.

Quantitative Brain Amyloid PET.

Since the development of amyloid tracers for PET imaging, there has been interest in quantifying amyloid burden in the brains of patients with Alzheimer disease. Quantitative amyloid PET imaging is poised to become a valuable approach in disease staging, theranostics, monitoring, and as an outcome measure for interventional studies. Yet, there are significant challenges and hurdles to overcome before it can be implemented into widespread clinical practice. On November 17, 2022, the U.S. Food and Drug Administration, Society of Nuclear Medicine and Molecular Imaging, and Medical Imaging and Technology Alliance cosponsored a public workshop comprising experts from academia, industry, and government agencies to discuss the role of quantitative brain amyloid PET imaging in staging, prognosis, and longitudinal assessment of Alzheimer disease. The workshop discussed a range of topics, including available radiopharmaceuticals for amyloid imaging; the methodology, metrics, and analytic validity of quantitative amyloid PET imaging; its use in disease staging, prognosis, and monitoring of progression; and challenges facing the field. This report provides a high-level summary of the presentations and the discussion.

Discriminant Potential of the Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog) in Greek Older Adults with Subjective Cognitive Decline and Mild Cognitive Impairment.

Alzheimer's Disease Assessment Scale Cognitive Subscale (ADAS-Cog) is a widely used screening tool for detecting older adults with Alzheimer's disease among their cognitively healthy peers. A previous study in Greek population showed that ADAS-Cog-Greek (G) is a valid tool and can identify people with Alzheimer's disease from older adult control group; however, there is no current data about whether ADAS-Cog can differentiate older adults with mild cognitive impairment (MCI) from those who have subjective cognitive decline (SCD). The current study aimed to examine the discriminant potential of ADAS-Cog-G in Greek older adults who meet the criteria for SCD or MCI. Four hundred eighty-two community-dwelling older adults, visitors of the Greek Alzheimer Association and Related Disorders, were enrolled in the current study. One hundred seventy-six of them met the criteria for SCD and three hundred six had MCI. Path analysis applied to the data showed that age, as well as educational level affected ADAS-Cog-G performance. Results showed that the cut-off scores, which better discriminate people with SCD from MCI as well as their sensitivity and specificity values, were extracted in participants with high educational level (13 educational years<) and mainly under the age of 75 years. The current study provided evidence concerning the discriminant potential of ADAS-Cog-G to differentiate older adults with SCD from those with MCI in the Greek population, and therefore contributes to the relevant literature on the field.

Safety and efficacy of acupuncture for mild cognitive impairment: a study protocol for clinical study.

Mild cognitive impairment (MCI) is an intermediary condition between typical cognitive decline that occurs owing to aging and dementia. It is necessary to implement an intervention to slow the progression from MCI to Alzheimer's disease. This manuscript reports the protocol for a clinical trial on the effect of acupuncture in patients with MCI. The trial will be a randomized, prospective, parallel-arm, active-controlled trial. Sixty-four patients with MCI will be randomized to the Rehacom or acupuncture group (n = 32 each). The participants in the acupuncture group will receive electroacupuncture at GV24 (Shenting) and GV20 (Baihui) and acupuncture at EX-HN1 (Sishencong) once (30 min) a day, twice per week for 12 weeks. The patients in the Rehacom group will receive computerized cognitive rehabilitation using RehaCom software once (30 min) daily, twice weekly for 12 weeks. The primary outcome measure is the change in the Montreal Cognitive Assessment Scale score. The secondary outcome measures are the Geriatric Depression Scale, Alzheimer's Disease Assessment Scale-Korean version-cognitive subscale-3 scores, and European Quality of Life Five Dimensions Five Level Scale. The safety outcomes will include the incidence of adverse events, blood pressure, blood chemistry parameters, and pulse rate. The efficacy outcome will be assessed at baseline and at six weeks, 13 weeks, and 24 weeks after baseline. The findings of this protocol will provide information regarding the effects of acupuncture on MCI. https://cris.nih.go.kr/cris/search/detailSearch.do?search_lang=E&focus=reset_12&search_page=M&pageSize=10&page=undefined&seq=25579&status=5&seq_group=25579, KCT0008861.

Translation from Preclinical Research to Clinical Trials: Brain-Gut Photobiomodulation Therapy for Alzheimer's Disease.

Recently, novel non-pharmacological interventions, such as photobiomodulation (PBM) therapy, have shown promise for the treatment of Alzheimer's disease (AD). This article outlines the translation from the preclinical to clinical stages of an innovative brain-gut PBM therapy in a mouse model of AD, a pilot clinical trial involving mild-to-moderate AD patients, and a continuing pivotal clinical trial with a similar patient population. In a mouse model of AD (Aβ25-35), daily application of brain-gut PBM therapy to both the head and the abdomen produced a neuroprotective effect against the neurotoxic effects of an Aβ25-35 peptide injection by normalizing all the modified behavioral and biochemical parameters. The pilot clinical trial to evaluate brain-gut PBM therapy demonstrated the tolerability and feasibility of the novel PBM-based treatment for mild-to-moderate AD patients. Compared to the sham patients, the PBM-treated patients had lower Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog) comprehension sub-scores, higher forward verbal spans, and lower Trail Making Test (TMT) Part B (TMT-B) execution times, which suggest an improvement in cognitive functions. This pilot study provided important information for the design of a novel pivotal clinical trial, currently in progress, to assess the efficacy of brain-gut PBM therapy in a larger sample of AD patients. This pivotal clinical trial could demonstrate that brain-gut PBM therapy is a safe, well-tolerated, and efficient disease-modifying treatment for mild-to-moderate AD patients and that it has medical and economic benefits.

Efficacy and safety of gantenerumab in the treatment of Alzheimer's disease: A meta-analysis of randomized controlled trials

IntroductionGantenerumab has garnered considerable attention for its potential to modify the natural course of Alzheimer's disease. However, recent studies have shown mixed results for the use of this medication for the treatment of Alzheimer's Disease. Therefore, this review compared the effects of Gantenerumab with placebo in patients with Alzheimer's disease. MethodsLiterature searches were conducted in PubMed, Embase and Cochrane database from inception to December 2023. Two independent authors (MS and LV) performed the study selection, data extraction and quality assessment. The outcomes of this review were: Clinical Dementia Rating - Sum of Boxes (CDR-SB), the Alzheimer's Disease Assessment Scale (ADAS-Cog), the Mini-Mental State Evaluation (MMSE) and the incidence of Amyloid-Related Imaging Abnormalities with Edema (ARIA-E) or Amyloid-Related Imaging Abnormalities with Hemosiderosis (ARIA-H). Meta-analysis were performed using Review Manager 5.4 (Cochrane Collaboration). ResultsFour studies reporting data for 2,848 patients were included in this review. The lenght of follow-up assessments ranged from 50 to 104 weeks. When compared to placebo, Gantenerumab was significantly associated with a lower ADAS-Cog score (MD -1.05; 95 % CI: -1.85 to -0.25) and lower MMSE score (MD -0.31; 95 % CI: -0.55 to -0.07). There were no differences in the CDR-SB score. Gantenerumab group had a higher incidence of ARIA-E (RR 8.94; 95 % CI: 6.22 to 12.84). ConclusionGantenerumab showed negative effects on cognitive outcomes of people with Alzheimer's Disease. There was a higher incidence of ARIA-E and ARIA-H for gantenerumab. Additional high quality studies are needed to draw more robust conclusions about this treatment.

Predicting the reversion from mild cognitive impairment to normal cognition based on magnetic resonance imaging, clinical, and neuropsychological examinations.

Reversion from mild cognitive impairment (MCI) to normal cognition (NC) is not uncommon and indicates a better cognitive trajectory. This study aims to identify predictors of MCI reversion and develop a predicting model. A total of 391 MCI subjects (mean age=74.3years, female=61%) who had baseline data of magnetic resonance imaging, clinical, and neuropsychological measurements were followed for two years. Multivariate logistic analyses were used to identify the predictors of MCI reversion after adjusting for age and sex. A stepwise backward logistic regression model was used to construct a predictive nomogram for MCI reversion. The nomogram was validated by internal bootstrapping and in an independent cohort. In the training cohort, the 2-year reversion rate was 19.95%. Predictors associated with reversion to NC were higher education level (p=0.004), absence of APOE4 allele (p=0.001), larger brain volume (p<0.005), better neuropsychological measurements performance (p<0.001), higher glomerular filtration rate (p=0.035), and lower mean arterial pressure (p=0.060). The nomogram incorporating five predictors (education, hippocampus volume, the Alzheimer's Disease Assessment Scale-Cognitive score, the Rey Auditory Verbal Learning Test-immediate score, and mean arterial pressure) achieved good C-indexes of 0.892 (95% confidence interval [CI], 0.859-0.926) and 0.806 (95% CI, 0.709-0.902) for the training and validation cohort. Observational duration is relatively short; The predicting model warrant further validation in larger samples. This prediction model could facilitate risk stratification and early management for the MCI population.

Comparative Efficacy and Safety of Monoclonal Antibodies for Cognitive Decline in Patients with Alzheimer's Disease: A Systematic Review and Network Meta-Analysis.

Recent clinical trials of anti-Aβ monoclonal antibodies (mAbs) in the treatment of early Alzheimer's disease (AD) have produced encouraging cognitive and clinical results. The purpose of this network meta-analysis (NMA) was to compare and rank mAb drugs according to their efficacy and safety. PubMed, Embase, Web of Science, and the Cochrane Library were searched for randomized controlled trials testing various mAbs for the treatment of cognitive decline in patients with AD, up to March 31, 2023. R software (version 4.2.3) along with JAGS and STATA software (version 15.0) were used for statistical analysis. Odds ratio (OR) for binary variables, mean difference (MD) for continuous variables, and their 95% confidence intervals (CI) were utilized to estimate treatment effects and rank probabilities for each mAb in terms of safety and efficacy outcomes. We calculated the surface under the cumulative ranking area (SUCRA) to evaluate each mAb, with higher SUCRA values indicating better efficacy or lower likelihood of adverse events. Thirty-three randomized controlled trials with a total of 21,087 patients were included in the current NMA, involving eight different mAbs. SUCRA values showed that aducanumab (87.01% and 99.37%, respectively) was the most likely to achieve the best therapeutic effect based on the changes of Mini-Mental State Examination (MMSE) and Clinical Dementia Rating scale Sum of Boxes (CDR-SB) scores. Donanemab (88.50% and 99.00%, respectively) performed better than other therapies for Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog) and Positron Emission Tomography-Standardized Uptake Value ratio (PET-SUVr). Lecanemab (87.24%) may be the most promising way to slow down the decrease of Alzheimer's Disease Cooperative Study-Activities of Daily Living (ADCS-ADL) score. In the analysis of the incidence of adverse events (subjects with any treatment-emergent adverse event), gantenerumab (89.12%) had the least potential for adverse events, while lecanemab (0.79%) may cause more adverse events. Solanezumab (95.75% and 80.38%, respectively) had the lowest incidence of amyloid-related imaging abnormalities characterized by edema and effusion (ARIA-E) and by cerebral microhemorrhages (ARIA-H) of the included immunotherapies. While SUCRA values provided a comprehensive measure of treatment efficacy, the inherent statistical uncertainty required careful analysis in clinical application. Despite immunotherapies significantly increasing the risks of adverse events and ARIA, the data suggest that mAbs can effectively improve the cognitive function of patients with mild and moderate AD. According to the NMA, aducanumab was the most likely to achieve significant improvements in different cognitive and clinical assessments (statistically improved MMSE and CDR-SB), followed by donanemab (statistically improved ADAS-Cog, and PET-SUVr) and lecanemab (statistically improved ADCS-ADL).

Can Brain Volume-Driven Characteristic Features Predict the Response of Alzheimer's Patients to Repetitive Transcranial Magnetic Stimulation? A Pilot Study.

This study is a post-hoc examination of baseline MRI data from a clinical trial investigating the efficacy of repetitive transcranial magnetic stimulation (rTMS) as a treatment for patients with mild-moderate Alzheimer's disease (AD). Herein, we investigated whether the analysis of baseline MRI data could predict the response of patients to rTMS treatment. Whole-brain T1-weighted MRI scans of 75 participants collected at baseline were analyzed. The analyses were run on the gray matter (GM) and white matter (WM) of the left and right dorsolateral prefrontal cortex (DLPFC), as that was the rTMS application site. The primary outcome measure was the Alzheimer's disease assessment scale-cognitive subscale (ADAS-Cog). The response to treatment was determined based on ADAS-Cog scores and secondary outcome measures. The analysis of covariance showed that responders to active treatment had a significantly lower baseline GM volume in the right DLPFC and a higher GM asymmetry index in the DLPFC region compared to those in non-responders. Logistic regression with a repeated five-fold cross-validated analysis using the MRI-driven features of the initial 75 participants provided a mean accuracy of 0.69 and an area under the receiver operating characteristic curve of 0.74 for separating responders and non-responders. The results suggest that GM volume or asymmetry in the target area of active rTMS treatment (DLPFC region in this study) may be a weak predictor of rTMS treatment efficacy. These results need more data to draw more robust conclusions.

Clinical variables contributing to the identification of biologically defined subgroups within cognitively unimpaired and mild cognitive impairment individuals.

A lack of consensus exists in linking demographic, behavioral, and cognitive characteristics to biological stages of dementia, defined by the ATN (amyloid, tau, neurodegeneration) classification incorporating amyloid, tau, and neuronal injury biomarkers. Using a random forest classifier we investigated whether 27 demographic, behavioral, and cognitive characteristics allowed distinction between ATN-defined groups with the same cognitive profile. This was done separately for three cognitively unimpaired (CU) (112 A-T-N-; 46 A+T+N+/-; 65 A-T+/-N+/-) and three mild cognitive impairment (MCI) (128 A-T-N-; 223 A+T+N+/-; 94 A-T+/-N+/-) subgroups. Classification-balanced accuracy reached 39% for the CU and 52% for the MCI subgroups. Logical Delayed Recall (explaining 16% of the variance), followed by the Alzheimer's Disease Assessment Scale 13 (14%) and Everyday Cognition Informant (10%), were the most relevant characteristics for classification of the MCI subgroups. Race and ethnicity, marital status, and Everyday Cognition Patient were not relevant (0%). The demographic, behavioral, and cognitive measures used in our model were not informative in differentiating ATN-defined CU profiles. Measures of delayed memory, general cognition, and activities of daily living were the most informative in differentiating ATN-defined MCI profiles; however, these measures alone were not sufficient to reach high classification performance.